1. Field of the Invention
The present invention relates to pharmaceutical formulations for use in the administration of medicaments by inhalation. In particular, the present invention relates to pharmaceutical formulations for use in pressurized metered dose inhalers (MDIs). The present invention also relates to methods for the preparation of said pharmaceutical formulations and to the use thereof in therapy.
2. Discussion of the Background
Pressurized metered dose inhalers (pMDIs) are well known devices for administering pharmaceutical active ingredients to the respiratory tract by inhalation. They consist of containers containing multiple doses, e.g., tens or even hundreds of doses, and each of these doses is delivered by a suitable metering valve.
Formulations for pMDIs typically consist of suspensions or solutions of one or more active substances in a liquefied propellant which is utilized to expel solid particles or droplets respectively containing the active ingredient to the respiratory tract as an aerosol.
The most commonly used aerosol propellants are hydrofluoroalkanes (HFAs; known also as hydrofluorocarbons or HFCs), in particular, 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227).
The efficiency of an aerosol device, such as a pMDI, is a function of the dose deposited at the appropriate site in the lungs. Deposition is affected by several factors, of which one of the most important is the aerodynamic particle size. Solid particles and/or droplets in an aerosol formulation can be characterized by their mass median aerodynamic diameter (MMAD).
Respirable particles are generally considered to be those with a MMAD less than 5 micron.
Active substances commonly delivered by inhalation include bronchodilators such as beta-2 adrenoreceptor agonists and anticholinergics, corticosteroids, anti-allergics and other active ingredients that may be efficiently administered by inhalation, thus increasing the therapeutic index and reducing side effects of the active material.
Formoterol, i.e., 2′-hydroxy-5′-[(RS)-1-hydroxy-2{[(RS)-p-methoxy-α-methylphenethyl]amino}ethyl]formanilide, particularly its fumarate salt, is a well known beta-2 adrenoreceptor agonist currently used clinically in the treatment of bronchial asthma and related disorders.
Beclometasone dipropionate is a potent anti-inflammatory steroid, named (8S,9R,10S,11S,13S,14S,16S,17R)-9-chloro-11-hydroxy-10,13,16-trimethyl-3-oxo-17-[2-(propionyloxy)acetyl]-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthren-17-yl propionate, available under a wide number of brands for the prophylaxis and/or treatment of inflammatory respiratory disorders.
Co-administration of formoterol fumarate and beclometasone dipropionate by pressurised metered dose inhalers (pMDI's) has significant advantages in the treatment and control of asthma.
The currently marketed formulation contains both active ingredients dissolved in a mixture of HFA134a and ethanol as co-solvent.
When the formulation is in the form of solution, the volumetric contribution of suspended drug particles is absent and much finer liquid droplets clouds, largely defined by the drug concentration in the solution, are generated.
The major advantage of said solution formulation is related to the presence of the corticosteroid in solution as the fine droplets exhibit an improved lung deposition and improved penetration into the bronchioloalveolar distal part of the respiratory tree wherein inflammation is known to play a role in spontaneous exacerbations of asthma symptoms.
However, although it has the apparent pH adjusted according to the teaching of WO 01/89480 for improving its chemical stability, due to the limited stability of formoterol in solution, said formulation can be stored for no longer than 15 months at a refrigerator temperature (from +2 to +8° C.) and for no longer than 5 months at room temperature.
These stability features are not optimal, in particular in sub-tropical and tropical countries.
HFA formulations wherein formoterol is present as suspended particles would obviously encounter lesser problems of chemical stability.
On the other hand, the amount of ethanol useful for solubilizing the corticosteroid may not be appropriate or optimal for ensuring the physical stability of a suspended drug. It is indeed well known that if the suspended drug has a slight solubility in the medium, a process known as Ostwald ripening can lead to particle size growth. The effect of Ostwald ripening may be particularly severe for a drug such as formoterol which needs to be formulated in low doses.
In view of the aforementioned problems, it would be highly advantageous to provide an aerosol pharmaceutical formulation for pMDIs comprising formoterol and beclometasone dipropionate, being both chemically and physically stable to allow a longer shelf-life at room temperature than the formulation of the prior art.